Circulating interleukin 10 and interleukin-6 serum levels in rheumatoid arthritis patients treated with methotrexate or gold salts: Preliminary report

In order to evaluate the relationship between serum concentrations of interleukin-10 (IL-10), IL-6, and acute phase proteins in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) or intramuscular gold (IMG) we determined IL-10, IL-6, C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP) and alpha-1-antichymotrypsin (ACT) in the sera of 35 RA patients. IL-10 and IL-6 levels were evaluated using an enzyme-linked immunoassay (ELISA). AGP and ACT level were measured using rocket immunoelectrophoresis. IL-10 serum level was not increased in RA patients as compared to controls (58.7 ± 18.1 pg/ml vs. 57.2 ± 11.9 pg/ml). IL-6 level was significantly elevated (91.6 ± 46.9 pg/ml vs. 45 ± 19 pg/ml, p < 0.05). CRP was significantly increased as compared to healthy controls (35 ± 19 mg/l vs. 3 ± 2 mg/l, p < 0.05). Patients treated with MTX or IMG presented an increased level of IL-10 and decreased amounts of IL-6, as compared to those treated with NSAID only. However, only changes between patients treated with IMG and NSAID were found to be statistically significant. A good negative correlation between IL-10 and IL-6 serum level was found (r = –0.75, p < 0.05). A positive significant correlation between IL-6 serum level and CRP (r = 0.62, p < 0.05), AGP (r = 0.78, p < 0.05) and ACT (r = 0.45, p < 0.05) was established. On the other hand, a negative correlation between IL-10 and serum level of CRP (r = –0.76, p < 0.05), AGP (r = –0.64, p < 0.05) and ACT (r = –0.38, p < 0.05) was also observed. Moreover, these relationships were maintained when patients treated with MTX, IMG, or NSAID were analyzed independently. According to the data thus far obtained, it seems that IL-10 decreases IL-6 production, and thereby indirectly affects the acute phase response, decreasing CRP, AGP, and ACT concentration in RA patients.Abbreviations ACT -1-antichymotrypsin - AGP ₁-acid glycoprotein - APP acute phase protein - CRP C-reactive protein - CSF colony stimulating factor - IFN interferon - IL interleukin - IMG intramuscular gold - MTX methotrexate - NSAID non-steroidal anti-inflammatory drug - RA rheumatoid arthritis     

Muscle spindles in rheumatoid arthritis

Summary Ultrastructural features of muscle spindles were studied in biopsy material from 100 patients suffering from classical rheumatoid arthritis. Thickening of the outer capsule, increased amount of extracellular ground substance within the inner capsule, and marked thickening of the basement membrane of capillary blood vessels supplying the muscle spindles were observed. Chronic inflammatory cells and macrophages were present within the spindles. Changes affecting the intrafusal muscle fibres were also seen. They were manifest as atrophy and degeneration of the intrafusal muscle fibres, absence of the specialised junctional complexes, and of the intercellular bridges, microladders and satellite cells. It is suggested that the changes affecting the intrafusal muscle fibres are probably secondary. Damage to the myelinated nerves was present, while the sensory and motor nerve endings were well preserved.Temporary Research Fellow the Rotterdam Centre for Rheumatic Disease Present address: Division of Pathology, Department of Obstetrics and Gynaecology, University of Chicago, Chicago, Illinois 60637, USA     

Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review

Background

We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis.

Does Hemopoietic Stem Cell Transplantation Have a Role in Treatment of Severe Rheumatoid Arthritis?

Based on animal models and limited clinical experience, there is considerable interest in use of high-dose immunosuppression followed by hemopoietic stem cell transplantation as treatment for severe rheumatoid arthritis. Because of its relatively low treatment-related mortality and morbidity, autologous transplantation is a more attractive option than allogeneic transplantation for initial clinical trials, even though anecdotal reports suggest that allogeneic transplantation has a greater likelihood of bringing about long-term disease control. The approach remains experimental with many unanswered questions such as the value and safety of high-dose therapy without transplantation, the need for T cell purging, the possible deleterious effects of post-transplant hemopoietic growth factors and the potential of mini allogeneic transplantation (a process whereby intense immunosuppression is combined with less intense myelosuppression). To achieve quick progress it is essential that clinical trials be carefully designed with all cases being reported to the Autoimmune Disease Stem Cell Project Database.     

A Morphological and Immunohistochemical Study of Lymphoid Germinal Centers in Synovial and Lymph Node Tissues from Rheumatoid Arthritis Patients with Special Reference to Complement Components and Their Receptors

Rheumatoid arthritis (RA) is one of the immune complex (IC) diseases in which lymphoid germinal centers (GCs) are found in the synovial tissue. Simultaneously, patients with RA often show swelling of lymph nodes. The morphology and function of the lymph node GCs in patients with RA is not clear. The aim of this study was to evaluate the differences in morphology and immunoreactions to complement (C) components, their receptors, and lgM-rheumatoid factor (RF) between synovial GCs and lymph-node GCs in RA. Furthermore, the relationship between these immuno-reactive substances and follicular dendritic cells (FDCs) in GCs was investigated. The tissues examined were 41 RA synovial specimens, seven RA lymph nodes with massive lymphadenopathy, and 10 non-RA lymph nodes. The number of synovial GCs was relatively decreased in comparison with lymph-node GCs in RA, and the diameter of each synovial GC was smaller than that of each lymph-node GC. The synovial GCs were edematous and less cellular, and moreover, those from RF-seronegative cases were smaller than those from RF seropositive cases. On the other hand, the lymph-node GCs in RA were larger, more cellular and hyperplastic, but contained more tingible-body macro-phages (TBMs) and neutrophils. In the GCs of both synovial tissues and lymph nodes in RA, early C components (C1q, C4, C3c, C3d), IgM RF, and C3b receptor (C3bR) and C3d receptor (C3dR) were expressed as a lacy network by light microscopy, and were demonstrated on the surfaces of FDCs and lymphocytes, and in the intercellular spaces by electron microscopy. Furthermore, immuno-staining for dendritic reticulum cells (DRC, DAKO DRC1) was observed in a lacy pattern by light microscopy and on the cell surface of FDCs by electron microscopy. In the GCs of non-RA lymph nodes, early C components, C3bR, C3dR, and DRC showed a similar reaction pattern, but IgMRF did not. Consequently, no marked difference in immunoreactions in the GCs, except for the immunoreactions of late C components, was found between synovial tissues and lymph nodes in RA. On the basis of these findings, we discuss the possibility of the presence of a RF-IC.     

Cytokine production profile of splenocytes derived from zymosan A-treated SKG mice developing arthritis

Objective SKG mice have a point mutation of the zeta-associated protein of 70 kD (ZAP-70) and spontaneously develop a severe polyarthritis in the conventional condition, whereas they are healthy under the specific pathogen free (SPF) condition. The purpose of this study was to investigate the cytokine production from splenocytes in SKG mice developing arthritis under the SPF condition. Material SKG and BALB/c mice were intraperitoneally injected with zymosan A under the SPF condition. Spleen was isolated 1, 2 or 8 weeks after the intraperitoneal injection of saline or zymosan A. Splenocytes were cultured with concanavalin A. Cytokine production and proliferation were measured 48 and 72 h after the culture. Results An intraperitoneal injection of zymosan A induced severe polyarthritis with increased levels of rheumatoid factor and interleukin 6 (IL-6) only in SKG mice. Splenocytes from SKG mice did not proliferate well maybe because of less productivity of IL-2. The IL-4 production from splenocytes of SKG mice was higher, while interferon-γ production was lower than those of BALB/c mice. An injection of zymosan A reduced the IL-4 production only in SKG mice. Conclusions SKG mice do not develop arthritis under the SPF condition possibly because of a low proliferative activity of T cells and Th2-predominance. Received 27 December 2005; returned for revision 7 February 2006; accepted by A. Falus 10 March 2006     

Inflammatory cytokine levels in paw tissues during development of rat collagen-induced arthritis: Effect of FK506, an inhibitor of T cell activation

Objective and design: To characterize rat collagen-induced arthritis (CIA) on the basis of levels of inflammatory cytokines, tumor necrosis factor (TNF)-, interleukin (IL)-1 and IL-6 in paw tissues, and further investigate the effect of FK506 (tacrolimus), a potent inhibitor of T cell activation, on cytokine levels.Methods: CIA was induced in female Lewis rats. The volume of hindpaws was measured before and after collagen immunization. TNF-, IL-1 and IL-6 levels in paw tissue extracts were determined by ELISA. Proteoglycan contents of cartilage in femoral heads was measured as an indication of cartilage destruction. To assess the effect of FK506 on inflammatory cytokine levels, rats were orally treated with 5 mg/kg of FK506 from days 14–21.Results: TNF- a level in paw tissues did not significantly change compared to levels found before collagen immunization, throughout development of CIA. In contrast, IL-1 and IL-6 levels in paw tissues significantly increased between day 14 and day 28 after collagen imuninization, when the arthritis was at a developed stage. Therapeutic treatment with FK506 reduced the elevated level of IL-6, but not IL-1, in paw tissue. FK506 treatment was effective in suppressing paw swelling and also recovering the loss of proteoglycan contents in the cartilage.Conclusions: Levels of IL-1 and IL-6, but not TNF- , in paw tissue were upregulated in association with the development of arthritis in rat CIA. These results suggest that IL-1 and IL-6, rather than TNF- , may play important roles at local inflammatory sites in producing joint destruction in rat CIA. FK506 may improve arthritis in established stages of CIA, by reducing the elevated level of IL-6.Received 4 March 2004; returned for revision 2 April 2004; accepted by M. J. Parnham 9 April 2004     

The role of COX-2 in angiogenesis and rheumatoid arthritis

Recent evidence suggests that cyclooxygenase (COX)-2 is a mediator of angiogenesis, and COX-2 activity is known to be upregulated in the rheumatoid arthritis (RA) synovium. We examined whether mediation of angiogenesis by COX-2 was occuring in cells of the RA synovium and in microvascular endothelial cells (ECs) that are similar to those found in the RA synovium. We demonstrate that rofecoxib, a selective COX-2 inhibitor, acts directly on human dermal microvascular ECs (HMVECs) to inhibit their chemotactic and tube forming ability. Likewise, pretreatment of HMVECs with rofecoxib significantly inhibited their ability to form tubes induced by conditioned media (CM) of activated RA synovial fibroblasts. When RA synovial fibroblasts were pretreated with rofecoxib for 16 h and then stimulated with interleukin (IL)-1beta, their CM induced significantly less HMVEC tube formation when compared with CM from vehicle-treated RA synovial fibroblasts. ELISAs performed on activated RA fibroblast CM for known proangiogenic factors demonstrated a significant reduction in bFGF, in addition to the expected decrease in PGE(2). Our studies suggest that COX-2-induced angiogenic activity is an active mechanism within diseased synovium and may provide an additional rationale for the use of COX-2 inhibitors in RA.     

Changes in extracellular potassium concentration in cat spinal cord in response to innocuous and noxious stimulation of legs with healthy and inflamed knee joints

Summary In 20 cats anaesthetized with alpha-chloralose and spinalized at the thoracolumbar junction we investigated the role of stimulation induced accumulation of extracellular potassium in the spinal cord in the processing of nociceptive discharges from the knee joint. For that we electrically stimulated the posterior articular nerve of the knee. We further performed innocuous and noxious stimulation of the knee and of other parts of the leg and studied the effect of an acute inflammation of the knee on [K⁺]₀ in the spinal cord. Innocuous stimulation of the skin (brushing or touching) and innocuous movements in the knee joint all induced rises in [K⁺]₀ which were maximal at recording depths of 1500 to 2200 m below the surface of the cord dorsum. Peak increases were 0.4 mM for touching the leg and 1.7 mM during rhythmic flexion/ extension of the knee joint. Noxious stimulation of the skin, the paw, the tendon and noxious movements of the knee joint also produced rises in [K⁺]₀, which were somewhat larger for the individual types of stimuli than those produced by innocuous intensities. Electrical stimulation of the posterior articular nerve induced rises in [K⁺]₀ by up to 0.6 mM. Stimulus intensities sufficient to activate unmyelinated group IV fibers were only slightly effective in raising [K⁺]₀ above the levels reached during stimulation of myelinated group II and III fibers. During development of an acute inflammation of the knee joint (induced by kaolin and carrageenan), increases in [K⁺]₀ and associated field potentials became larger by about 25%. We assume that this reflects an increase in neuronal responses. In conclusion, changes in [K⁺]₀ in the spinal cord are some-what larger during noxious stimulation than during innocuous stimulation. The absolute level reached depended more on the site and type of stimulation than on the actual stimulus intensity itself. Hence a critical role of spinal K⁺ accumulation for nociception is unlikely.